Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
  • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
  • A61K31/52—Purines, e.g. adenine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/60—Salicylic acid; Derivatives thereof
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/66—Phosphorus compounds
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
  • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
  • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/20—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/20—Pills, tablets, discs, rods
  • A61K9/2004—Excipients; Inactive ingredients
  • A61K9/2013—Organic compounds, e.g. phospholipids, fats
• • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
  • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
  • Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
  • Y10S930/00—Peptide or protein sequence
  • Y10S930/01—Peptide or protein sequence
  • Y10S930/27—Cyclic peptide or cyclic protein

Definitions

• the present invention relates to the oral delivery of polar bioactive agents particularly polypeptides which by this route are slowly absorbed and more especially to the enhancement of this delivery by formulations which contain a hydroxyaromatic acid.
• polar bioactive agents refers to those therapeutic substances which, due to their polar nature, are slowly absorbed from the gastrointestinal tract and include particularly, polypeptides which have three or more residues of amino acids with a molecular weight of 4000 or less.
• bioactive agents are so polar that they are only slowly absorbed from the gastrointestinal tract. Consequently, these agents, on the basis of the current art, must be administered by the intravenous or intramuscular route or in excessively large oral doses in order to attain clinical efficacy.
• other polar bioactive agents such as the polypeptides which, due to their hydrophilic nature, are also slowly absorbed from the gastrointestinal tract.
• the hydrophilic, polar nature of these agents precludes their rapid absorption so that even the small percentage which is absorbed is subject to a long residency time in the gastrointestinal environment where both acidic and enzymatic degradation contribute to their poor bioavailability. It is therefore clear that any factor which enhances the rate of absorption will demonstrate improved clinical efficacy.
• a major object of this invention is to provide a class of agents or adjuvants which enhance the oral absorption of polypeptides (polar bioactive agents).
• Another object is to provide a process utilizing said class of agents to enhance the oral absorption of polypeptides.
• Another object is to provide a stable drug form utilizing said class of agents which when administered orally will provide increased blood levels of the therapeutic agent.
• the present invention generally comprises the steps of preparing a drug form capable of being orally administered, wherein the drug form comprises an effective unit dosage amount of a polypeptide drug and a hydroxyaromatic acid or salt thereof, the hydroxyaromatic acid or salt thereof being present in the drug form in a sufficient quantity to be effective in enhancing the oral absorption rate and administering the drug form to warm-blooded animals.
• the amount of polypeptide varies over a wide range, but generally any therapeutically effective unit dosage amount of the selected polypeptide is used.
• hydroxyaromatic acids or their salts thereof that are used as the adjuvants in our method and in our drug forms have the following structural formulae including the various isomers possible within the formulae set forth: ##STR1## wherein R 1 is CO 2 H, --(CH 2 )--COOH, ##STR2## SO 3 H, or a pharmaceutically acceptable salt thereof such as the sodium salt or the calcium salt wherein R 2 is OH, H, a lower alkoxy radical including methoxy, ethoxy, butoxy, or octyloxy, a lower alkyl radical including methyl, isopropyl, ethyl, t-butyl, n-butyl, or t-octyl, a halo radical, or a tri-halo lower alkyl radical including trifluoromethyl, and wherein y is an integer of 1 or 2.
• More preferred adjuvants of Formula I are those compounds wherein the R 1 and OH groupings are ortho to each other.
• Such adjuvants are not considered novel per se and may be prepared by techniques known to those skilled in the art.
• the amount of adjuvant of Formula I used in our method and drug forms may vary over a wide range; in general, the identity and the amount of the adjuvant used in connection with the drug is such to be effective in enhancing the absorption rate of the drug from the gastrointestinal compartment into the bloodstream.
• the amount of adjuvant used per unit dosage of the particular drug being administered is in the range of 50 mg to 750 mg.
• the amount of adjuvant to be effective will vary depending on the particular drug used and the release characteristics of the particular dosage form used. (For example, a rapidly disintegrating drug delivery device or a slow release device will have different adjuvant requirements.)
• the effectiveness of the adjuvants becomes significant at local concentration exceeding 0.01% at the absorption site. Their use at a dosage whereby their concentration at the absorption site exceeds 5% is not recommended because of the local irritating effect on the tissue.
• polypeptide agents whose enhanced oral delivery is a subject of the present invention encompasses polypeptides having three (3) or more residues of amino acids and having a molecular weight of 4000 or less. Examples of polypeptides which fall within the above parameters are the following:
• the quantity of these polypeptide agents necessary for preparing the drug form could vary over a wide range, but would normally be regulated by that quantity necessary to comprise the therapeutically effective dosage form.
• the drug forms of this invention are suitably administered in oral dosage form, such as by tablet or capsule, by combining the polypeptide agent in a therapeutic amount and the adjuvant of Formula I in a sufficient quantity to be effective to enhance oral delivery with an oral pharmaceutically acceptable inert carrier, such as lactose, starch (pharmaceutical grade), dicalcium phosphate, calcium sulfate, Kaolin, mannitol and powdered sugar.
• an oral pharmaceutically acceptable inert carrier such as lactose, starch (pharmaceutical grade), dicalcium phosphate, calcium sulfate, Kaolin, mannitol and powdered sugar.
• an oral pharmaceutically acceptable inert carrier such as lactose, starch (pharmaceutical grade), dicalcium phosphate, calcium sulfate, Kaolin, mannitol and powdered sugar.
• the preferred dose form of the adjuvant of Formula I should be a pharmaceutically acceptable salt and the drug form should be designed to release the polypeptid
• binders include, without limitation, starch, gelatin, sugars such as sucrose, molasses, and lactose, natural and synthetic gums, such as acacia, sodium alginate, extract of Irish moss, carboxymethylcellulose, methylcellulose, and polyvinylpyrrolidone, polyethylene glycol, ethylcellulose and waxes.
• Typical lubricants for use in these dosage forms can include, without limitation, boric acid, sodium benzoate, sodium acetate, sodium chloride, leucine and polyethylene glycol.
• Suitable disintegrators can include, without limitation, starch, methylcellulose, agar, bentonite, cellulose and wood products, alginic acid, guar gum, citris pulp, carboxymethylcellulose, and sodium lauryl sulfate.
• a conventionally, pharmaceutically acceptable dye can be incorporated into oral dosage unit form, e.g., any of the standard FD & C dyes.
• the tablets were coated with 11 mg of pre-coat and 32 mg of enteric coating according to the coating procedure described below.
• Tablets or capsules were placed in a coating pan containing baffles to provide adequate tumbling. A small amount of the coating solution was applied using an air sprayer and the solvents evaporated with a warm air supply directed into the coating pan. This procedure was repeated until the desired amount of coating material was applied. The amount of coating material was determined from the weight gain of a representative group of tablets.
• Pre-coat A film of hydroxypropylmethylcellulose was applied to the tablets followed by an enteric coating.
• Enteric coat A film of hydroxypropylmethyl- cellulosephthalate was applied.
• the drug was administered at 10 mg/ml unless otherwise noted and the adjuvant at 20 mg/ml unless otherwise noted.
• the (AUC)i.v. was determined for each drug, based on the mean value from 3-6 animals.

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• Health & Medical Sciences (AREA)
• Chemical & Material Sciences (AREA)
• Life Sciences & Earth Sciences (AREA)
• Veterinary Medicine (AREA)
• Medicinal Chemistry (AREA)
• Pharmacology & Pharmacy (AREA)
• Epidemiology (AREA)
• Animal Behavior & Ethology (AREA)
• General Health & Medical Sciences (AREA)
• Public Health (AREA)
• Engineering & Computer Science (AREA)
• Molecular Biology (AREA)
• Chemical Kinetics & Catalysis (AREA)
• General Chemical & Material Sciences (AREA)
• Oil, Petroleum & Natural Gas (AREA)
• Biophysics (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Medicinal Preparation (AREA)
• Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
• Cosmetics (AREA)
• Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
• Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)

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Cited By (60)

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• 1981
  • 1981-02-25 NZ NZ196349A patent/NZ196349A/en unknown
  • 1981-02-26 PT PT72576A patent/PT72576B/pt not_active IP Right Cessation
  • 1981-03-03 IE IE454/81A patent/IE50984B1/en not_active IP Right Cessation
  • 1981-03-04 GR GR64314A patent/GR74442B/el unknown
  • 1981-03-04 AU AU68057/81A patent/AU556734B2/en not_active Ceased
  • 1981-03-05 CA CA000372394A patent/CA1165689A/en not_active Expired
  • 1981-03-06 DE DE8181101644T patent/DE3170684D1/de not_active Expired
  • 1981-03-06 ES ES500186A patent/ES500186A0/es active Granted
  • 1981-03-06 ZA ZA00811515A patent/ZA811515B/xx unknown
  • 1981-03-06 DK DK102181A patent/DK102181A/da not_active Application Discontinuation
  • 1981-03-06 EP EP81101644A patent/EP0036145B1/en not_active Expired
  • 1981-03-06 AT AT81101644T patent/ATE13487T1/de active
  • 1981-03-07 JP JP3194281A patent/JPS56166849A/ja active Pending
• 1982
  • 1982-06-11 US US06/387,410 patent/US4462991A/en not_active Expired - Fee Related

Patent Citations (1)

Non-Patent Citations (12)

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